Calcium(II) selectively induces α-synuclein annular oligomers via interaction with the C-terminal domain

Rachel Lowe, Dean L. Pountney, Poul Henning Jensen, Wei Ping Gai, Nicolas H. Voelcker

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Abstract

α-Synuclein filaments are the major component of intracytoplasmic inclusion bodies characteristic of Parkinson's disease and related disorders. The process of α-synuclein filament formation proceeds via intermediate or protofibrillar species, each of which may be cytotoxic. Because high levels of calcium(II) and other metal ions may play a role in disease pathogenesis, we investigated the influence of calcium and other metals on α-synuclein speciation. Here we report that calcium(II) and cobalt(II) selectively induce the rapid formation of discrete annular α-synuclein oligomeric species. We used atomic force microscopy to monitor the aggregation state of α-synuclein after 1 d at 4°C in the presence of a range of metal ions compared with the filament formation pathway in the absence of metal ions. Three classes of effect were observed with different groups of metal ions: (1) Copper(II), iron(III), and nickel(II) yielded 0.8-4 nm spherical particles, similar to α-synuclein incubated without metal ions; (2) magnesium(II), cadmium(II), and zinc(II) gave larger, 5-8 nm spherical oligomers; and, (3) cobalt(II) and calcium(II) gave frequent annular oligomers, 70-90 nm in diameter with calcium(II) and 22-30 nm in diameter with cobalt(II). In the absence of metal ions, annular oligomers ranging 45-90 nm in diameter were observed after 10 d incubation, short branched structures appeared after a further 3 wk and extended filaments after 2-3 mo. Previous studies have shown that α-synuclein calcium binding is mediated by the acidic C terminus. We found that truncated α-synuclein (1-125), lacking the C-terminal 15 amino acids, did not form annular oligomers upon calcium addition, indicating the involvement of the calcium-binding domain.

Original languageEnglish
Pages (from-to)3245-3252
Number of pages8
JournalProtein Science
Volume13
Issue number12
DOIs
Publication statusPublished - 1 Dec 2004
Externally publishedYes

Keywords

  • α-synuclein
  • Amyloid
  • Atomic force microscopy
  • Calcium
  • Fibrillogenesis
  • Lewy body
  • Parkinson's disease

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